Substance use disorders are a serious public health problem with medical, societal, and economic costs exceeding $800B annually. Rates of tobacco, alcohol, and illicit drug (e.g., stimulants, and opioids) use among veterans are as high or higher than those observed in civilian populations. Despite long-standing efforts to develop pharmacotherapies to treat substance use disorders, few pharmacotherapies exist for nicotine, opioid, or alcohol use disorders, and there are currently no US Food and Drug Administration (FDA)-approved pharmacotherapies for stimulant abuse. This relative lack of pharmacotherapies for substance use disorders is likely due to a variety of factors; however, the time and costs associated with identifying viable targets and developing effective treatment strategies has discouraged many companies/individuals from entering this space. One strategy to reduce the time and costs required to get candidate medications into the clinic is to leverage knowledge about the neurobiological substrates of addiction to rationally repurpose drugs already approved by the FDA for other indications to treat substance abuse. Given the central role for dopamine (DA) in reward, reinforcement, and addiction, we have focused our efforts on identifying targets, such as 5-HT2C and DA D3 receptor (R)s, that are capable of modulating the activity of the mesolimbic DA system. Indeed, strong preclinical evidence from our laboratory and others suggests that targeting each of these receptors with FDA-approved drugs (lorcaserin [Belviq], a serotonin [5-HT]2CR agonist; and buspirone [Buspar], a DA D3R antagonist/5-HT1A agonist) can reduce the abuse-related effects of a variety of drugs (e.g., cocaine, methamphetamine, oxycodone, fentanyl, nicotine, and alcohol). In addition, we have recently shown that the effectiveness of these drugs to reduce drug taking are synergistically enhanced when the drugs are administered in combination (i.e., mixtures of lorcaserin and buspirone are more potent/effective than either drug alone). Although promising, each of these drugs have dose-limiting (off-target) effects that reduce the likelihood that these effects will translate to the clinic. For instance, it is important to note that doses of lorcaserin only slightly larger than those approved/required to produce its therapeutic effects have been reported to producing feelings of ?high?, ?bad drug effect?, and ?hallucination? in humans; effects that are attributed to off-target actions at 5-HT2ARs. In addition to the off-target effects limiting the clinical utility of lorcaserin and buspirone for treating substance use disorder, the relatively ?dirty? pharmacology of lorcaserin and buspirone also complicates efforts to isolate the receptor and circuit-level mechanisms that account for these drugs (and drug mixtures) to effectively reduce drug taking behavior. Accordingly, proposed studies will combine intravenous drug self-administration with microinjections aimed at particular brain regions to evaluate the novel hypotheses that acute and repeated administration of fixed dose mixtures of highly selective, but experimental 5-HT2CR agonists (CP809101) and DA D3R antagonist (VK4-116) and partial agonists (BAK4-54) will be produce a synergistic reduction in both stimulant and opioid self-administration (Aim 1), and that these effects are mediated by a combined activation of 5-HT2CRs in the ventral tegmental area (VTA) and inhibition of DA D3Rs in the nucleus accumbens (NAcc) shell (Aim 2). In addition to providing important new information about the neurobiology of substance abuse, because this strategy involves modulation of the mesolimbic DA reward pathway by targeting 5-HT2C and DA D3 Rs, this novel approach will also guide efforts to develop a highly effective and broad-spectrum pharmacotherapy for substance (polysubstance) use disorders. Such a treatment would have significant implications for the health and well-being of millions of veterans.